PK/PD modelling of reversal of neuromuscular blockade by a chemically optimised cyclodextrin

Abstract

Org 25969 is a chemically optimised cyclodextrin designed for reversal of rocuronium-induced neuromuscular block (NMB). This investigation aims to develop a PK/PD model for the interaction of rocuronium and Org 25969. In a phase-I study subjects received various doses of Org 25969 alone or 3 minutes after rocuronium (0.6 mg.kg). The pharmacokinetics of both drugs were evaluated in conjunction with the effect on the AMG-derived TOF ratio. The results were analysed using a PK model in conjunction with a sigmoid Emax PD model in NONMEM. The PK of rocuronium and Org 25969 alone were best described with a 3-compartment model with linear elimination from the central compartment. A PK interaction model adequately predicted the observed increase in total rocuronium concentration after administration of Org25969. Optimisation of the binding constant Kd on the PK interaction data yielded a value of 0.21μM, which is close to the value of 0.1 μM by microcalorimetry in vitro. A Posterior Predictive Check validated the accuracy of the modelled effect of Org 25969 on rocuronium-induced NMB. In conclusion, the proposed model accurately predicts the PK and PD of the rocuronium-Org 25969 interaction, and the microcalorimetrically determined Kd value is a good predictor of the in vivo affinity constant. The potential drug-drug interactions with Org 25969 can therefore be effectively probed with simulations based on in vitro Kd values. Clinical Pharmacology & Therapeutics (2004) 75, P80–P80; doi: 10.1016/j.clpt.2003.11.306